This invention is directed to methods and compositions for prevention of immune defense suppression and augmenting natural defenses to cancer.
Despite nearly a century of intensive basic and clinical research, cancer remains one of the most dreaded diseases, still claiming hundreds of thousands of victims per year in the United States alone. Over the last few years, much work has been directed toward improving the body's natural defenses against cancer. The ability of certain lymphocytes to kill cancer cells is known generally as immune defense. See, generally, E. S. Golub and D. R. Green, "Immunology: A Synthesis" (Sinauer Associates, Sunderland, Nass.) 2d ed., 1991, Ch. 33, pp. 575-595, incorporated herein by this reference. Among the therapeutic methods intended to increase immune defense and thereby bolster the body's own defenses against cancer has been the administration of lymphokines such as interleukin-2 (IL-2), tissue necrosis factor .alpha. (TNF.alpha.), and interferons. Although it can be shown that these agents, when administered in vitro are capable of stimulating both natural killer (NK) and lymphokine-activated killer (LAK) activity, the use of lymphokines and/or other agents intended to stimulate natural immunity towards tumor cells has yielded erratic clinical results. (Mesler et al., "Large Scale Production of Human Lymphokine Activated Killer Cells for Use in Adoptive Immuno Therapy," J. Immunol. Meth. 88:265-275 (1986); T. L Whiteside, "Human Tumor-Infiltrating Lymphocytes and Their Characterization," in Interleukin-2 and Killer Cells in Cancer, Ch. 10, pp. 133-151; B. W. Hancock & R. C. Rees, "Interleukin-2 and Cancer Therapy," Cancer Cells 2:29-32 (1990)). Because lymphokines can produce serious side effects when used in high doses, there exists a need for a method of potentiating the effect of lymphokines and other immune-surveillance-stimulating agents in vivo in order to consequences of excessively high doses of these agents. Such a method would greatly improve cancer treatment and could be used in conjunction with other cancer therapies, such as radiation or chemotherapy. Such therapy also might prove of value in treatment of neoplasms in immunologically compromised individuals, such as those infected with the HIV virus, in whom cancers such as Kaposi's sarcoma, non-Hodgkin's lymphoma, and various carcinomas, frequently occur. There is thus a need to develop a more efficient method of immune defense that can assist the body in fighting cancer without excessively high and toxic doses of lymphokines.
It has been suggested that cancer cells may have defense mechanisms, which enable them to evade immune defense and resist or inactivate the cytolytic action of NK and LAK lymphocytes (R. Snyderman & G. J. Cianciolo, "Immunosuppressive Activity of the Retroviral Envelope Protein p15E and Its Possible Relationship to Neoplasia," in Immunology Today (J. Inglis, ed., Elsevier, Amsterdam, 1984). There is therefore a need for a method of blocking or reversing the defense mechanisms of cancer cells that allow them to evade immune defense by lymphocytes.